Aromatic mercury alcoholates of salts of hydroxy carboxylic acids



Patented Apr. 12, 1938 UNITED STATES AROMATIC MEROURY ALCOHOLATES OFSALTS 0F HYDROXY CARBOXYLIC ACIDS Carl N. Andersen, Wellesley Hills,Mass, assignor to Lever Brothers Company, a corporation of Maine NoDrawing. Application June 12, 1935,- Serial No. 26,248

17 Claims.

The present invention relates to the production of aromatic mercuryalcoholates of salts of hydroxy carboxylic acids.

It is an object of my invention to produce new organic mercury compoundsuseful as germicides and for other therapeutic purposes.

I have discovered that when the hydrogen atom ofa hydroxyl group in asalt of a hydroxy acid is replaced by the essential radical of certainaromatic mercury compounds, compounds are produced which haveextraordinarily high potency as antiseptics and germicides and at thesame time are characterized by relatively low toxicity and otherdesirable properties.

The compounds I have prepared may be described as having the generalformula (RHg) :cRl, in which It represents an aromatic structure to acarbon atom of which the mercury is directly attached; in which .7:represents the number of RHg groups in the compound, which may be one ormore; and in which R1 represents a radical corresponding to a salt of analiphatic or aromatic hydroxy acid that is linked to the RHg group orgroups through the replacement of a hydrogen atom of one or more hydroxygroups. While the words group and groups are used hereinafter it is tobe understood that these words must be interpreted as singular or pluraldepending on the value of at.

.More particularly, R represents an aromatic structure, which may be anaromatic nucleus with or without side chains, and the expressionaromatic structure used herein is intended to be generic and include anaromatic nucleus with or without side chains. The aromatic structure isof the type in which none of the nuclear or side chain carbon atoms hasdirect linkage with any element other than hydrogen, carbon or mercury.B may stand for the phenyl group, CsHs, or for an aromatic hydrocarbonhaving a nucleus similar to the phenyl hydrocarbons, as for example,polycyclic hydrocarbons, in which all of the nuclear carbon atoms, otherthan the one attached to mercury, and any side chain carbon atoms, havetheir valences satisfied either by carbon or hydrogen. Examples are thediphenyl, tolyl, xylyl, and naphthyl groups.

' In my applications Serial Nos.694,202 and 694,- 207, filed October 18,1933, I have shown that when a compound containing both the COOH and OHgroups is reacted with an aromatic mercury compound containing the abovedescribed radical, R1 .for example, the hydroxide or a soluble salt, thearomatic mercury radical replaces the hydrogen of theCOOl-I group toform aromatic mercury salts. I have now discovered that when thehydrogen of the COOH group in these compounds. is replaced by a metal toform a salt, and this salt is reacted with an aromatic mercury compoundof the above defined type, the aromatic mercury radical R will replacethe hydrogen of the OH group to form an aromatic mercury a1- coholate.

The radical R1 is an alcoholate radical of a salt of an aliphatic or anaromatic hydroxy acid. The acid may be mono or polybasic; if it ispolybasic the hydrogen of all of the COOH groups would be replaced by ametal or positive radical; The salt may contain one or more OH groups.If it contains a plurality, the hydrogen of one or more of the OH groupsmay be replaced by the aromatic mercury radical to form monoorpolyalcoholates respectively. Any metal or positive radical may besubstituted in the carboxyl group. If an alkali metal is. substituted,the compound, in general, is rendered more soluble and for many purposesthis is desirable. Bismuth and antimony are also particularly desirableas substituents in the carboxyl group because these metals often impartdesirable properties to the compounds.

The following examples are illustrative of the types of compoundsfalling within the above defined class: alcoholate of sodium salicylate,RI-IgOCsIth-COONa; alcoholate of potassium lactate, CI-Iz-CHOHgRi-COOK;alcoholate ,loi.

sodium lactate CHa-CHOHgRCOONe; mono-alcoholate of sodium tartrateNaOOC-CHOH-CHOI-IgR-COONa; alcoholate of sodium citrate,

COONaCHz COONaCOHgR- CHzCOONa tri-alcoholate of bismuth salicylate(RHgO- C6H4' COO) 3B1; tri-alcoholate of bismuth tartrate,

(C4I-I306HgR) 3Bi2 alcoholate of bismuth ammonium citrate,

(B10) (NI-I4) CeHsoflHgR;

monoalcoholate of bismuth lactate,

(CH3CHOH- COO) 2(CH3-CI-IOHgR-COO) Bi; alcoholate of bismuth tannate;mono-alcoholate of potassium antimonyl tartrate,

COOK-CHOI-IgR-CHOH-COO(SbO) HzO; alcoholate of sodium malate,

COONa CHOI-IgR- CH2 COONa; tri-alcoholate of sodium gallate,

COONa-CeHz- (OHgR) 3;

alcoholate of para-hydroxy sodium benzoate,

COONa CeH4 OHgR alcoholate of hydroxy sodium naphthoate,

COONa CioHs OI-IgR; di-alcoholate of sodium glycerate,

COONa- CHOHgR- CHzOHgR alcoholate of sodium glycollate,

RHgO CH2 COONa; and di-alcoholate of di-hydroxy sodium stearate,C17H33(OHgR) COONa.

I have prepared all of the above noted organic mercury alcoholates.These compounds together with others I have investigated comprise asufficiently representative number of the class to lead me to believethat aromatic mercury alcoholates corresponding to all the salts ofthese types can be prepared. The compounds so prepared have greater orlesser, but always in relative high degree, desirable antiseptic andgermicidal properties. I, therefore, regard my invention as generic toand including the entire group of aromatic mercury alcoholates of saltsof hydroxy acids of the above defined type.

The general method of producing these compounds consists in reactingtogether the salt of the hydroxy acid and a compound containing anaromatic mercury radical of the above mentioned type. A common solventfor both reacting components is employed. The compound resulting fromthe reaction in some instances is relatively insoluble as compared tothe reacting components and upon its precipitation it may be filtered,washed and dried. If the compound is not relatively insoluble thereaction mixture may be concentrated by evaporation to precipitate thecompound.

The aromatic mercury compound I prefer to use for reacting with thesalts of hydroxy acids is the hydroxide. This compound has the advantagethat water is the only other product of the reaction and the resultingcompound is, therefore, easily purified. I may also employ a solublearomatic mercury salt, for example, the acetate or the lactate, in thereaction with the salt of the hydroxy acid. The aromatic mercuryalcoholates produced are generally of low solubility as compared withthe aromatic mercury salt and are relatively insoluble as compared withthe salt of the hydroxy acid.

Lhe following examples are given as illustrative of the process by whichall the compounds of this group may be prepared and as illustrative andrepresentative of organic mercury alcoholates falling within the scopeof my invention:

Example 1 17.64 grams of phenylmercury hydroxide is dissolved in twoliters of water and heated until solution is complete. The solution isfiltered to remove any insoluble or foreign material. To the filtrate isadded 9.6 grams of sodium salicylate dissolved in 50 cc. of water. Themixture is filtered and concentrated to about 400 cc. and again filteredwhile hot and allowed to cool. A white precipitate settles out oncooling. The mixture is filtered and the precipitate is washed well withwarm water and alcohol, and dried. The resulting material melts at162-168 C. and is the phenylmercury alcoholate of sodium salicylate.

Example 2 17.64 grams of phenylmercury hydroxide are dissolved in oneliter of water and heated until solution is complete. The solution isthen filteredto remove any insoluble material. To the filtrate is added7.68 grams of potassium lactate dissolved in cc. of water. Noprecipitate results and the solution is filtered and concentrated to asmaller volume. When the solution is cooled, crystals separate, whichare removed by filtration, washed and dried. Upon recrystallization ofthe material from alcohol it sinters at 196 C. and melts to an opaquemass at 208-2l0 C. It is the phenylmercury alcoholate of potassiumlactate.

Example 3 35.28 grams of phenylmercury hydroxide are dissolved in oneand one-half liters of water and heated until solution is complete. Thesolution is filtered to remove any insoluble material. To the filtrateis added 42.84 grams of sodium citrate dissolved in 200 cc. of water.The solution is concentrated to one-half its volume and an abundantyield of crystals separate. These are removed by filtration, washed anddried. Upon recrystallization from alcohol the material sinters at 212C. and melts to an opaque mass at 217- 218 C. It is the phenylmercuryalcoholate of sodium citrate.

Example 4 a Example 5 17.64 grams of phenylmercury hydroxide aredissolved in one liter of alcohol and heated until solution is complete.The solution is then filtered to remove any insoluble material. To thefiltrate is added 21.16 grams of bismuth lactate suspended in 500 cc. ofalcohol. The mixture is heated for a short time and then allowed tocool. A precipitate forms, which is separatedby filtration. washedwithalcohol and dried. Upon heating the material it darkens at C; andblackens at 230-235 C with decomposition. It is the phenylmercuryalcoholate of bismuth lactate.

Example 6 17.64: grams of phenylmercury hydroxide are dissolved in oneliter of water and heated until solution is-complete. The solution isfiltered to remove any insoluble material. To the filtrate is addedl9.22 grams of antimony potassium tartrate (tartar emetic) dissolved in100 cc. of water. A white precipitate forms immediately and the mixtureis heated for a few minutesafter which it is allowed to cool. Theprecipitate is separated by filtration, washed and dried. Upon beingrecrystallized from alcohol it does not melt up to 280 C. butdecomposition becomes apparent at this point. It is themono-phenylmercury alcoholate of antimony. potassium tartrate.

Example 7 52.92 grams of phenylmercury hydroxide are dissolved in twoliters of water and heated until solution is completed. The solution isfiltered to remove any insoluble material. To the filtrate remove anyinsoluble material.

is added a solution of sodium gallate which has been prepared by aneutralization of 11.28 grams of gallic acid in water with an aqueoussolution of 2.4 grams of sodium hydroxide. A light green precipitateforms and the mixture is heated for a few minutes and allowed to cool.The precipitate is separated by filtration, washed well with water andalcohol and dried. Upon recrystallization from alcohol, a white powderycrystalline material is obtained which melts at 116-11'7 C. at whichpoint decomposition sets in. It is the tri-phenylmercury alcoholate ofsodium gallate.

Example 8 11.28 grams of 3-hydroxy,2-naphthoic acid are dissolved in cc.of alcohol and neutralized .with 2.4 grams of sodium hydroxide in 50 cc.of

the phenylmercury alcoholate of hydroxy sodium naphthoate.

7 Example 9 58.8 grams of phenylmercury hydroxide are dissolved in twoliters of water and heated until solution is complete. The solution isfiltered to In a separate container 32.8 grams of di-hydroxy stearicacid is suspended into 200 cc. of water and treated with 4 grams ofsodium hydroxide dissolved in 50 cc. of water to form di-hydro-xy sodiumstearate. This solution is added to the phenylmercury hydroxide solutionand a precipitate results. The mixture is heated for a short time toinsure completion of the reaction and is then allowed to cool. Theprecipitate is separated by filtration, washed well with water and a fewcc. of alcohol and dried. Upon recrystallization from alcohol thematerial melts at 139139.5 C. It is di(pheny1mercury) alcoholate ofdi-hydroxy sodium stearate.

The reacting materials are employed in substantially theoreticalquantities. In cases where it is desired to replace the hydrogen of morethan one hydroxyl group correspondingly larger quantities of thearomatic mercury compound will be required. If it is desired, in someinstances, 10% excess of the salt may be employed in order to insure thecomplete conversion of the phenylmercury compound, particularly ininfstances where the salt is readily soluble.

ample, room temperature.

Any suitable solvent in which the reacting components are soluble may beused for carrying out the reaction. If they are both soluble in waterthis is generally used for reasons of convenience but if not, othersolvents, such as the alcohols or acetone or mixtures of these with eachother or with water, may be employed. The process may be carried out atany temperature, for ex- In most cases I find, however, that the use ofheat facilitates the solution of the reacting components and speeds thereaction.

From the description of the specific examples it will be readilyapparent to one skilled in the art how the other members of the group ofsalts of hydroxy acids may be reacted with aromatic mercury compounds toproduce aromatic mercury alcoholates of analogous structure.

All of the compounds produced as above described are characterized byextraordinarily high potency as germicides. Tests to determine theefficacy of some of them in killing B. typhosus and Staph. aureus werecarried out under the following conditions.

Aqueous solutions of varying dilutions from l:10,000 upward untilkilling ceased, were made up.

These dilutions were employed in the conduct of the tests by thefollowing methods:

Circular 198, U. S. Dept. of Agriculture, Dec. 1931, described as F. D.A. method against Eberthella; typhi (typhoid bacillus) at 37 C. and F.D. A. special method against Staph. aureus at 37 C.

As illustrative of the potency of the compounds, the killing power ofthe following is given merely as illustrative. The figures represent themaximum dilutions at which killing in 15 minutes. resulted:

In addition to their high germicidal value, these compounds arecharacterized by relatively low toxicity. Because of these properties itis possible to use them in extreme dilutions and in many situationswhere known germicides, because of toxic or other undesired properties,cannot be employed. They may be used externally and locally, and in somecases administered internally with satisfactory results from thegermicidal stand point and without harmful effect to the body or itsfunctions.

The compounds retain their germicidal activity when incorporated in soapand various menstrums employed in preparing germicidal compositions.

When these new compounds are to be used directly as germicides they maybe employed in aqueous or other solutions or they may be formed intovarious preparations such as mouth washes, tooth pastes, soaps,ointments, etc.

I claim:

1. A new aromatic mercury alcoholate having the general formula (RHg)R1,in which R. represents an aromatic structure to a carbon atom of whichthe mercury is directly attached, and in which none of the carbon atomshas direct linkage with any element other than hydrogen, carbon andmercury; in which R1 represents a radical of an alkali-metal salt of apoly-hydroxy aliphatic carboxylic acid, which radical is linked to theRI-Ig group by replacement of a hydrogen of an OH group, and in which :nrepresents the number of RI-Ig groups in the compound, and is an integerof at least one and. not more than the number of OH groups in said salt.

2. A new aromatic mercury alcoholate having the general formula (RI-lg)1R1, in which R represents an aromatic structure to a carbon atom ofwhich the mercury is directly attached, and in which none of the carbonatoms has direct linkage with any element other than hydrogen, carbonand mercury; in which R1 represents a radical of an alkali metal salt ofa poly-hydroxy monobasic carboxylic acid which radical is linked to theRHg group by replacement of a hydrogen of an OH group, and in which :1:represents the number of RHg groups in the compound, and is an integerof at least one and not more than the number of OH groups in said salt.

3. A new aromatic mercury alcoholate having the general formula RHgRr,in which R represents an aromatic structure to a carbon atom of whichthe mercury is directly attached, and in which none of the carbon atomshas direct linkage with any element other than hydrogen, carbon andmercury; and in which R1 represents a radical of an alkali-metal salt ofa mono-hydroxy aromatic carboxylic acid, which radical is linked to theRI-Ig group by replacement of a hydrogen of the OH group.

4. A new phenylmercury alcoholate having the general formula (CeHsHg)1R1, in which R1 represents a radical of an alkali-metal salt in apolyhydroxy aliphatic carboxylic acid, which radical is linked to theCsI-IsI-Ig group by replacement of a hydrogen of an OH group, and inwhich a: represents the number of CcHsI-Ig groups in the compound, andis an integer of at least one and not more than the number of OH groupsin said salt.

5. A new phenylmercury alcoholate having the general formula(C6H5Hg)xR-1, in which R1 represents a radical of an alkali-metal saltof a polyhydroxy mono-basic carboxylic acid, which radical is linked tothe CeHsI-Ig group by replacement of a hydrogen of an OH group, and inwhich :1: represents the number of C6H5Hg groups in the compound, and isan integer of at least one and not more than the number of OH groups insaid salt.

6. A new phenylmercury alcoholate having the general formula CSHSHgRI,in which R1 represents a radical of an alkali-metal salt of amonohydroxy aromatic carboxylic acid which radical is linked to theCsHsHg group by replacement of the hydrogen of the OH group.

'7. Phenylmercury alcoholate of potassium lactate.

8. Phenylmercury alcoholate of sodium salicylate.

9. Diphenylmercury alcoholate of dihydroxy sodium stearate.

10. A new aromatic mercury alcoholate having the general formula(RHg)xR1, in which R represents an aromatic structure to a carbon atomof which the mercury is directly attached, and in which none of thecarbon atoms has direct linkage with any element other than hydrogen,car- Icon and mercury; in which R1 represents a radical of an alkal-metal salt of a hydroxy carboxylic acid, which radical is linked to theRHg group by replacement of hydrogen of the OH group; and in which Erepresents the number of RHg groups in the compound and is an integer ofat least one and not more than the number of OH groups in said salt.

11. A new aromatic mercury alcoholate having the general formula (RHg):cRi, in which R represents an aromatic structure to a carbon atom ofwhich the mercury is directly attached, and in which none of the carbonatoms has direct linkage with any element other than hydrogen, carbonand mercury; in which R1 represents a radical of an alkali-metal salt ofan aliphatic hydroxy carboxylic acid, which radical is linked to the RHggroup by replacement of hydrogen of the OH group; and in which asrepresents the number of RI-Ig groups in the compound and is an integerof at least one and not more than the number of OH groups in said salt.

12. A new aromatic mercury alcoholate having the general formula (RHgMRin which R represents an aromatic structure to a carbon atom of whichthe mercury is directly attached, and in which none of the carbon atomshas direct linkage with any element other than hydrogen, car bon andmercury; in which R1 represents a radical of an alkali-metal salt of anaromatic hydroxy carboxylic acid, which radical is linked to the RHggroup by replacement of hydrogen of the OH group; and in which .1:represents the number of RHg groups in the compound and is an integer ofat least one and not more than the number of OH groups in said salt.

13. A new aromatic mercury alcoholate having the general formula (RHg)1R1, in which R represents an aromatic structure to a carbon atom ofwhich the mercury is directly attached, and

in which none of the carbon atoms has direct linkage with any elementother than hydrogen, carbon and mercury; in which R1 represents aradical of an alkali-metal salt of a hydroxy monobasic carboxylic acid,which radical is linked to the RHg group by replacement of hydrogen ofthe OH group; and in which :n represents the number of RI-Ig groups inthe compound and is an integer of at least one and not more than thenumber of OH groups in said salt.

14. A new phenylmercury alcoholate having the general formula(CsI-I5Hg)xR1, in which R1 represents a radical of an alkali-metal saltof a hydroxy carboxylic acid, which radical is linked to the CsI-IsI-Iggroup by replacement of hydrogen of the OH group; and in which 1,represents the r number of CsI-IsHg groups in the compound and is aninteger of at least one and not more than the number of OH groups insaid salt.

15. A new phenylmercury alcoholate having the general formula(C6H5I'Ig)a:Rl, in which R1 rep- 1 resents a radical of an alkali-metalsalt of an aliphatic hydroxy carboxylic acid, which radical is linked tothe CeHtHg group by replacement of hydrogen of the OH group; and inwhich x represents the number of C6H5Hg groups in the compound and is aninteger of at least one and not more than the number of OH groups insaid salt.

16. A new phenylmercury alcoholate having the general formula(C6H5Hg)a:R1, in which R1 represents a radical of an alkali-metal saltof an aromatic hydroxy carboxylic acid, which radical is linked to thecsHsHg group by replacement of hydrogen of the OH group; and in which a:represents the number of CsI-IsI-Ig groups in the compound and is aninteger of at least one and not more than the number of OH groups insaid salt.

1'7. A new phenylmercury alcoholate having the general formula (C6H5Hg)1R1, in which R1 represents a radical of an alkali-metal salt of ahydroxy mono-basic carboxylic acid, which radical is linked to theC6H5Hg group by replacement of hydrogen of the OH group; and in which asrepresents the number of CGIIEHg groups in the compound and is aninteger of at least one and not more than the number of OH. groups insaid salt.

CARL N. ANDERSEN.

